M.I.4 Primary and secondary coenzyme Q10 deficiency

Abstracts / Neuromuscular Disorders 17 (2007) 764–900 mtDNA instability; (b) defects of mtDNA translation; (c) defects of coenzyme Q biosynthesis. The first group comprises Mendelian traits characterized by either the accumulation of multiple mtDNA deletions or tissuespecific mtDNA depletion. Mutations in polymerase gamma, the core enzyme of mtDNA replication, and in several other factors related to mtDNA maintenance, are responsible for a continuum clinical spectrum ranging from autosomal dominant or recessive PEO, to spino-cerebellar ataxia with epilepsy, to Alpers’ syndrome. The second group comprises severe encephalopathies caused by mutations in mitochondrial translation factors, but also a peculiar multisystemic disease characterized by mitochondrial myopathy with lactic acidosis and sideroblastic anemia. MLASA is caused by mutations in pseudouridylate synthase 1, an isomerase that converts uridine into pseudouridine of both cytosolic and mitochondrial tRNAs. The third group consists of primary CoQ10 deficiency, a potentially treatable condition with a clinical spectrum that encompasses at least five major phenotypes. Mutations in the CoQ10 biosynthetic genes, COQ2, PDSS1, and PDSS2, have been identified in children with severe multisystemic disease, while the other forms still await genetic characterization.

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chondria contain their own genome, mtDNA, which is present in multiple copies in each cell. Mutations of the mitochondrial genome may either affect all copies of the genome (homoplasmic mutations) or only some copies (heteroplasmic mutations). The development of new (somatic) mutations is of particular interest because of the potential role of these mutations in certain types of muscle disease and in the ageing process. In some patients with nuclear genetic defects involving the maintenance of the mitochondrial genome or involved in nucleotide metabolism, somatic mtDNA mutations are common and result both in evidence of mitochondrial dysfunction and muscle weakness. The treatment of mitochondrial myopathies remains a huge challenge, at least in part because of our inability to manipulate the mitochondrial genome in vitro or in vivo. Some of the complications of mitochondrial myopathies are amenable to supportive therapies, but correcting the defect is not possible at present. Current research is focussed on trying to develop methods to prevent the transmission of mtDNA disease and to correct the genetic defect. One approach for somatic mtDNA mutations may be to activate muscle satellite cells, since these cells do not appear to contain the mtDNA mutation and thus regenerating muscle will be potentially unaffected.

doi:10.1016/j.nmd.2007.06.017 doi:10.1016/j.nmd.2007.06.019

M.I.4 Primary and secondary coenzyme Q10 deficiency Hirano, M. * Columbia University Medical Center, New York, United States

NEW DEVELOPMENTS IN METABOLIC DISORDERS OF MUSCLE (INCLUDING DISORDERS OF GLYCOGEN, LIPIDS AND MITOCHONDRIA); ORAL PRESENTATIONS

Coenzyme Q10 (CoQ10) is a lipid-soluble component of virtually all cell membranes and has multiple metabolic functions including the transport of electrons from mitochondrial respiratory chain complexes I and II to complex III. Deficiency of CoQ10 is an autosomal recessive syndrome with four major phenotypes: (1) encephalomyopathy characterized by the triad of recurrent myoglobinuria, brain involvement and ragged-red fibers; (2) severe infantile multisystemic disease; (3) cerebellar ataxia; and (4) isolated myopathy. The diversity of clinical presentations of CoQ10 deficiency suggests etiological heterogeneity, which has, in fact, been demonstrated by the identification of mutations in multiple genes. Mutations in the CoQ10 biosynthetic genes, PDSS1, PDSS2, and COQ2 have been identified in four families with infantile-onset disorders, predominantly encephalomyopathies with nephrotic syndrome. In addition, CoQ10 deficiency can be secondary as demonstrated by the association of APTX mutations, which cause ataxia oculomotor apraxia (AOA1) with deficiency of CoQ10 while mutations in electron-transferring flavoprotein dehydrogenase (ETF-DH) have been identified with the pure myopathic form of CoQ10 deficiency. Deficiency of CoQ10 is best detected in muscle biopsies or cultured fibroblasts, but blood levels of CoQ10 are not reliable to diagnose this condition. Defects of mitochondrial respiratory chain enzyme complexes I + III and II + III with normal activities of the individual enzymes is a clue to diagnose CoQ10 deficiency. Patients with all forms of CoQ10 deficiency have shown clinical improvements after initiating oral CoQ10 supplementation. Thus, early diagnosis is of critical importance in the management of these patients.

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doi:10.1016/j.nmd.2007.06.018

M.I.5 Somatic mtDNA mutations in health and disease and a futuristic approach towards therapy Turnbull, D. * Newcastle University, Mitochondrial Research Group, Newcastle, United Kingdom Mitochondria are essential intracellular organelles responsible for generating the majority of ATP required for normal muscle function. Mito-

Muscular manifestations of very long-chain acyl-coenzyme A dehydrogenase deficiency: A clinical, and biochemical study in 12 patients Laforeˆt, P. 1,*; Acquaviva-Bourdain, C. 2; Rigal, O. 3; Brivet, M. 4; Pe´nisson-Besnier, I. 5; Chabrol, B. 6; Chaigne, D. 7; Boespflug-Tanguy, O. 8; Laroche, C. 9; Bedat-Millet, A. 10; Lombe`s, A. 11; Andresen, B. 12; Eymard, B. 1; Vianey-Saban, C. 2 1 Institut de Myologie, Hoˆpital Pitie´-Salpeˆtrie`re, AP-HP, Paris, France; 2 Centre de Re´fe´rence des Maladies He´re´ditaires du Me´tabolisme, Centre de Biologie Est, Bron, France; 3 Department of Biochemistry, Hoˆpital Robert-Debre´, AP-HP, Paris, France; 4 Department of Biochemistry, Hoˆpital de Biceˆtre, AP-HP, Le Kremlin-Biceˆtre, France; 5 Centre de Re´fe´rence Maladies Neuromusculaires Nantes-Angers, CHU d’Angers, Angers, France; 6 Centre de Re´fe´rence des Maladies Me´taboliques de l’Enfant, CHU Timone, AP-HP de Marseille, Marseille, France; 7 Clinique Sainte-Odile, Strasbourg, France; 8 Service de Neuroge´ne´tique-Neurope´diatrie, INSERM UMR 384, Clermont-Ferrand, France; 9 De´partement de Pe´diatrie Me´dicale, Hoˆpital Universitaire Dupuytren, Limoges, France; 10 Department of Neurology, CHU de Rouen, Rouen, France; 11 Institut de Myologie, INSERM U 582, Paris, France; 12 Research Unit for Molecular Medicine, Aarhus University, Aarhus, Denmark Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an increasingly recognized defect of mitochondrial long-chain fatty acid b-oxidation due to the spreading of tandem mass spectrometry (MS/MS). Severe phenotypes have been reported in childhood, but predominant muscular manifestations may also occur in adults. We report the clinical, biochemical and molecular studies in 12 adult patients from 9 different families with VLCAD deficiency. Clinical and biochemical data were retrospectively collected. VLCAD defect was demonstrated in cultured skin fibroblasts or in lymphocytes. Seven women and four men are still followed-up (mean age: 31 years). One man died accidentally. All patients exhibited exercise intolerance and recurrent rhabdomyolysis episodes, triggered by strenuous exercise, fasting, cold or fever (mean age at onset: 10 years). Severe general manifestations also occurred during childhood in three patients. Muscle biopsies showed a mild lipidosis in only 3/9 cases. Carnitine levels were lowered in 7/9 patients and reduced palmitate oxidation was observed in 7/11 patients. Increased levels of cis-5-tetradecenoic acid and tetradecenoylcarnitine (C14:1) were observed in all patients, even